Function of mesothelial cells in the tumor microenvironment of pancreatic ductal adenocarcinoma

间皮细胞在胰腺导管腺癌肿瘤微环境中的功能

• 批准号: 10372149
• 负责人: Huocong Huang
• 金额: $ 11.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10372149
• 关键词: Address; Adhesions; Antibody-drug conjugates; Antigens; CD4 Positive T Lymphocytes; Cells; Clinical; Cues; Data; Disease; Drug Delivery Systems; Embryo; Epithelial Cells; Exclusion; Extracellular Matrix; Fibroblasts; Fibrosis; Genes; Immune Evasion; Immunosuppression; Immunotherapy; Impairment; In Vitro; Inflammatory; Interleukin-1; Malignant Neoplasms; Membrane; Mesenchymal; Mesoderm; Mesothelial Cell; Mesothelium; Monoclonal Antibodies; Myocardial Infarction; Operative Surgical Procedures; Organ; Outcome; Pancreatic Ductal Adenocarcinoma; Pathologic; Peripheral; Peritoneal; Phase; Phenotype; Physiological; Population; Preclinical Testing; Process; Reporting; Resistance; Signal Pathway; Solid Neoplasm; Source; Surface; Survival Rate; System; T cell regulation; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Training; Transforming Growth Factor beta; Tumor Volume; Tumor-infiltrating immune cells; Vaccines; anti-cancer; cancer cell; chemotherapy; chimeric antigen receptor T cells; combat; immune checkpoint blockade; immune resistance; in vivo Model; lipid biosynthesis; mesothelin; mouse genetics; neglect; novel; novel strategies; prevent; single-cell RNA sequencing; targeted cancer therapy; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; wound healing

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA) is a lethal disease characterized by extensive desmoplasia caused by the rapid expansion of cancer-associated fibroblasts (CAFs), resulting in the formation of dense stroma. CAFs stimulate cancer progression by secreting a variety of factors that support cancer cells and facilitate immunosuppression. In addition, they also secrete extracellular matrix (ECM) that provides survival and invasion cues to cancer cells and impairs drug delivery. Recently, several populations of CAFs with distinct functions have been characterized in PDA by our group and others using single cell RNA sequencing (scRNA seq). One population is characterized as myofibroblastic CAFs (myCAFs), another population is characterized as inflammatory CAFs (iCAFs), the third population was first identified as antigen-presenting CAFs (apCAFs), which express MHC II molecules and can effectively present antigen to T cells. My preliminary data demonstrated that apCAFs are mesothelial cells. Mesothelial cells form a continuous layer of epithelial cells known as mesothelium. The mesothelium is traditionally thought to be a membrane providing a non-adhesive surface covering organs and tissues. However, until the description of apCAF population, mesothelial cells have been neglected as a potential functional constituent of the tumor microenvironment. My preliminary data suggest that during PDA progression, mesothelial cells go through a mesothelial-fibroblastic transition (MFT), in which they down-regulate MHC II molecules that are required for CD4+ T cells activation, and up-regulate fibroblast genes that have been known to prevent T cell infiltration and activation. Peripheral T cell exclusion is a major immune evasion phenotype in PDA, and my preliminary data show that this exclusion occurs at the region where mesothelial cells are transitioning to CAFs. Therefore, MFT might be an important mechanism of immune evasion and understanding this process is critical. In this proposal, I will test the hypothesis that the fibroblastic transition of mesothelial cells promotes immune evasion in PDA and identify potential strategies to inhibit this process. I propose the following two aims: Aim 1. Determine the fate of mesothelial cells during PDA progression. Aim 2. Determine the functions of MFT on immune evasion. The outcome of the proposed study has the potential to shift the paradigm of tumor microenvironment studies, identify novel strategies to target CAFs and overcome resistance of immune therapies in PDA and other tumor types.

项目总结/摘要 胰腺导管腺癌（PDA）是一种致死性疾病，其特征是广泛的结缔组织增生， 通过癌症相关成纤维细胞（CAF）的快速扩张，导致致密基质的形成。 CAF通过分泌多种支持癌细胞并促进癌细胞增殖的因子来刺激癌症进展。 免疫抑制此外，它们还分泌细胞外基质（ECM），其提供存活和 入侵线索癌细胞和损害药物输送。最近，几个群体的CAFs与不同的 我们的研究小组和其他研究小组已经使用单细胞RNA测序（scRNA）对PDA中的功能进行了表征 seq）。一个群体被表征为成肌纤维细胞CAF（myCAF），另一个群体被表征为成肌纤维细胞CAF（myCAF）。 作为炎症性CAF（iCAF），第三个群体首先被确定为抗原提呈CAF（apCAF）， 其表达MHCII分子并能有效地将抗原呈递给T细胞。我的初步数据 证明apCAF是间皮细胞。间皮细胞形成一层连续的上皮细胞 称为中胚层。传统上认为间皮是一种提供非粘附性粘附的膜。 覆盖器官和组织的表面。然而，在描述apCAF群体之前，间皮细胞 作为肿瘤微环境的潜在功能成分一直被忽视。我的初步数据 提示在PDA进展过程中，间皮细胞经历间皮-成纤维细胞转变（MFT）， 其中它们下调CD 4 + T细胞活化所需的MHCII分子，并上调CD 4 + T细胞活化所需的MHCII分子。 已知成纤维细胞基因可防止T细胞浸润和活化。外周血T细胞排斥反应是 一个主要的免疫逃避表型在PDA，我的初步数据显示，这种排斥发生在 中间皮层细胞向CAF过渡的区域。因此，MFT可能是一个重要的机制 免疫逃避和理解这一过程至关重要。在这个建议中，我将测试假设， 间皮细胞的成纤维细胞转化促进PDA的免疫逃避，并确定潜在的 策略来抑制这一过程。我提出以下两个目标：目标1。决定间皮细胞的命运 PDA进展过程中的细胞。目标2.确定MFT对免疫逃避的作用。成果 这项研究有可能改变肿瘤微环境研究的范式， 靶向CAF和克服PDA和其他肿瘤类型免疫疗法耐药性的策略。